Multiple Myeloma Is it now a curable disease

Multiple Myeloma: Is it now a curable disease? Pritesh Patel, MD

OVERVIEW • Disease overview • How I approach initial treatment • Treatment considerations at relapse

HOW MANY PEOPLE ARE AFFECTED BY MYELOMA? ≈96, 000 MM patients National Cancer Institute Survival Epidemiology and End Results Program SEER Cancer Statistics Review 1975 -2012. Available at seer. cancer. gov accessed 4/30/16

HOW MANY PEOPLE ARE AFFECTED BY MYELOMA? ≈30, 000 new diagnoses National Cancer Institute Survival Epidemiology and End Results Program SEER Cancer Statistics Review 1975 -2012. Available at seer. cancer. gov accessed 4/30/16

MYELOMA CELLS Impaired immune system M Protein Grow in bone marrow Bone related signs and symptoms Anemia 10 -35% Lytic Lesions 70% Bone High blood Pain calcium 50% 15 -20% Infection 15% Kidney failure 25 -30% Neuropathy 5%

Production and release of clonal immunoglobulin into blood and/or urine Destruction and invasion of bone marrow cavity Impaired immune function High blood calcium and bone complications

WHAT IS THE “M PROTEIN”? Heavy chain Light chain Protein normally made by plasma cells Single type produced by myeloma cells Can be measured at diagnosis in urine and blood Level can be tracked for disease response and relapse

THE NATURAL HISTORY OF MYELOMA Smoldering Myeloma MGUS Late Myeloma Early Myeloma Plasma Cell Leukemia M-PROTEIN 100 Asymptomatic Symptomatic Active myeloma 50 20 2 ND RELAPSE 1 ST RELAPSE 1 st line PLATEAU REMISSION TIME “Operational” cure

QUESTIONS AT DIAGNOSIS 1) Do I have SYMPTOMATIC myeloma? 2) What is my prognosis/ stage etc? 3) Am I eligible for stem cell transplant? 4) What initial treatment?

BONE MARROW PLASMA CELLS >10% OR BIOPSY PROVEN PLASMACYTOMA AND ONE OF THE FOLLOWING C S R Li A M B Hypercalcemia: >11 mg/d. L or 1 mg/d. L higher than Sixty ULN percent or greater plasma cells in bone marrow Renal impairment: >2 mg/d. L or clearance <40 ml/min Light chain ration of >100 Anemia: >2 g/d. L below LLN or < 10 g/d. L MRI lesion >5 mm Bone lesions: >1 bone lesion on CT, PET or x ray, osteopenia

BASELINE TESTING Complete blood count Complete chemistry B 2 microglobulin and albumin Electrophoresis, immunofixation, free light chains Bone marrow aspirate and biopsy • FISH testing • Cytogenetics Skeletal survey Consideration of MRI and PET/CT

5 YEAR SURVIVAL 60 50 40 30 20 10 19 75 19 77 19 79 19 81 19 83 19 85 19 87 19 89 19 91 19 93 19 95 19 97 19 99 20 01 20 03 20 05 20 07 0 National Cancer Institute Survival Epidemiology and End Results Program SEER Cancer Statistics Review 1975 -2012. Available at seer. cancer. gov accessed 4/30/16

HOW IS MYELOMA STAGED? STAGE CRITERIA I β 2 microglobulin <3. 5 mg/d. L Albumin >3. 5 g/d. L AND Normal LDH AND standard risk karyotype II Neither stage I or II III β 2 microglobulin >5. 5 mg/d. L AND EIITHER high LDH OR high risk karyotype

WHO CAN UNDERGO STEM CELL TRANSPLANT? • Decision based largely on functional class and comorbid illness – Can be performed safely in many patients in 70 s • Patient choice

THE PRINCIPLE OF AUTOLOGOUS TRANSPLANT Cell freezing and storage Blood stem cell mobilization High dose melphalan Stem cell reinfusion Blood counts decrease then and recover

RISKS AND BENEFITS OF TRANSPLANT Benefits Prolonging remission “Cure” in some patients Risks Prolonged hospitalization Diarrhea and mucositis Infection

INITIAL TREATMENT- TRANSPLANT ELIGIBLE Induction 3 -6 cycles Auto Transplant Consolidation and maintenance

INITIAL TREATMENT- TRANSPLANT INELIGIBLE Induction Maintenance

CONSIDERATIONS IN INITIAL TREATMENT 2 vs. 3 Drugs Kidney function Convenience and Cost

COMMONLY USED MEDICATIONS • Blood sugar • Weight gain • Sleep distubance Steroids e. g. dexamethasone • Blood counts • DVT risk • Peripheral neuropathy Immunomodulatory drugs e. g. lenalidomide Proteasome inhibitors e. g. bortezomib

PRINCIPLE OF “MAINTENANCE” • Initial therapy reduces disease • Maintenance is a less intensive phase of therapy • Maintain remission as long as possible without significant compromise of quality of life

IFM 2009 PHASE III RANDOMIZED TRIAL N=700 Untreated Patients • Treatment: 8 cycles of lenalidomide, bortezomib, and dexamethasone (RVD) • Maintenance lenalidomide for 1 year • ASCT at relapse • Treatment: RVD x 3 cycles and ASCT • Consolidation: 2 cycles of RVD VS. • Maintenance: Lenalidomide for 1 year Conventional Arm ASCT arm • Results (f/u 39 months) – Complete remission 58% in ASCT arm vs. 46% in RVD arm – 3 -year PFS 61% in ASCT arm vs. 48% in RVD arm – Median OS similar at 3 years (88%) Attal, et al. Blood. 2015; 126: abst 391.

SUPPORTIVE CARE • Anti-infection prophylaxis – e. g. acyclovir with bortezomib • Anti-thrombotic prophylaxis – Risk factors include medications and immobility • Bone health – Bisphonates and calcium

CONSIDERATIONS IN RELAPSED MYELOMA • When to treat? • Which treatment to use? – Organ dysfunction – Side effects – Re-treatment

NEWLY APPROVED AGENTS FOR RELAPSED DISEASE New generation IMIDs Pomalidomide New generation proteasome inhibitors Carfilzomib Ixazomib Histone Deacetylase Inhibitors Panobinostat Monoclonal antibodies Daratumumab Elotuzumab

SUMMARY • Prolonged remissions are achievable in 2016 – Goal to achieve deep response – Maintained with less intense therapy • Now a large number of options at relapse